Postdoctoral Fellow Salk Institute La Jolla, California, United States
Abstract: Alzheimer’s disease (AD) is a severe neurodegenerative disorder that exclusively effects elderly people. Despite decades of research, AD remains a debilitating, progressive, and ultimately fatal dementia with no disease-modifying treatment options. This is partly due to the lack of human model systems that capture complex human genetics and human biological age. We have previously shown that induced neurons (iNs) directly converted from patient’s fibroblast overcome these limitations by retaining neuron-specific hallmarks of aging and reflect unifying sporadic AD-related signatures. Using a multi-omic approach, we showed that AD iNs have an increased population of senescent cells that have impaired electrophysiological activity, metabolic reprogramming, and most critically the gain of inflammatory senescence associated secretory phenotype (SASP) that could activate human glia. Our data indicate that chemical or genetic ablation of this minority population of cells could effectively eliminate the neuroinflammatory signature in AD iNs, highlighting senescence as a functional target for therapeutic interventions in AD. However, it is still unknown through what mechanism neurons, which aren’t a pro-inflammatory cell type, could gain this feature during senescence. Here, we provide evidence that late-life activation of the transposon long interspersed nuclear element 1 (LINE-1) underlies the initiation of a SASP in AD neurons. In addition to LINE-1 knockdown, interventions that eliminate LINE-1 reverse transcription reduce SASP expression, suggesting a cytoplasmic DNA sensing mechanism. Our data point to LINE-1 as the mechanism for gain-of-function in inflammation in senescence neurons, and a targetable candidate for reducing late-life neuroinflammation in AD.
